Alosetron Hydrochloride

1 INDICATIONS AND USAGE Alosetron tablets are indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal tract excluded, and not responded adequately to conventional therapy. Diarrhea-predominant IBS is severe if it includes diarrhea and one or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. Because of infrequent but serious gastrointestinal adverse reactions associated with alosetron tablets, the indication is restricted to those patients for whom the benefit-to-risk balance is most favorable. Clinical studies have not been performed to adequately confirm the benefits of alosetron tablets in men. Alosetron tablets are a selective serotonin 5-HT 3 antagonist indicated only for women with severe diarrhea-predominant irritable bowel syndrome (IBS) who have: chronic IBS symptoms (generally lasting 6 months or longer), had anatomic or biochemical abnormalities of the gastrointestinal tract excluded and not responded adequately to conventional therapy. (1) Severe IBS includes diarrhea and 1 or more of the following: frequent and severe abdominal pain/discomfort, frequent bowel urgency or fecal incontinence, disability or restriction of daily activities due to IBS. (1)

2 DOSAGE AND ADMINISTRATION Starting dose is 0.5 mg twice a day. (2.1) May increase dose to 1 mg twice a day after 4 weeks if starting dosage is well tolerated but does not adequately control IBS symptoms. (2.1) Discontinue alosetron tablets in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. (2.1) 2.1 Adult Patients To lower the risk of constipation, alosetron tablets should be started at a dosage of 0.5 mg twice a day. Patients who become constipated at this dosage should stop taking alosetron tablets until the constipation resolves. They may be restarted at 0.5 mg once a day. If constipation recurs at the lower dose, alosetron tablets should be discontinued immediately. Patients well controlled on 0.5 mg once or twice a day may be maintained on this regimen. If after 4 weeks the dosage is well tolerated but does not adequately control IBS symptoms, then the dosage can be increased to up to 1 mg twice a day. Alosetron tablets should be discontinued in patients who have not had adequate control of IBS symptoms after 4 weeks of treatment with 1 mg twice a day. Alosetron tablets can be taken with or without food [see Clinical Pharmacology (12.3) ] . Alosetron tablets should be discontinued immediately in patients who develop constipation or signs of ischemic colitis. Alosetron tablets should not be restarted in patients who develop ischemic colitis. Clinical trial and post-marketing experience suggest that debilitated patients or patients taking additional medications that decrease gastrointestinal motility may be at greater risk of serious complications of constipation. Therefore, appropriate caution and follow-up should be exercised if alosetron tablets are prescribed for these patients. Post-marketing experience suggests that elderly patients may be at greater risk for complications of constipation; therefore, appropriate caution and follow-up should be exercised if alosetron tablets are prescribed for these patients [see Warnings and Precautions (5.1) ] . 2.2 Patients with Hepatic Impairment Alosetron tablets are extensively metabolized by the liver and increased exposure to alosetron tablets are likely to occur in patients with hepatic impairment. Increased drug exposure may increase the risk of serious adverse reactions. Alosetron tablets should be used with caution in patients with mild or moderate hepatic impairment and is contraindicated in patients with severe hepatic impairment [see Contraindications (4) , Use in Specific Populations (8.6) ] .

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the label: Complications of constipation [see Boxed Warning, Warnings and Precautions (5.1) ] Ischemic colitis [see Boxed Warning, Warnings and Precautions (5.2) ] Most common adverse reactions (incidence > 2% and > placebo) in clinical studies were constipation, abdominal discomfort and pain, nausea and gastrointestinal discomfort and pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Patients with Irritable Bowel Syndrome: Table 1 summarizes adverse reactions from 22 repeat-dose studies in patients with IBS who were treated with 1 mg of alosetron hydrochloride twice daily for 8 to 24 weeks. The adverse reactions in Table 1 were reported in 1% or more of patients who received alosetron hydrochloride and occurred more frequently on alosetron hydrochloride than on placebo. A statistically significant difference was observed for constipation in patients treated with alosetron hydrochloride compared to placebo (p < 0.0001). Table 1: Adverse Reactions Reported in ≥ 1% of Patients with Irritable Bowel Syndrome and More Frequently on Alosetron Hydrochloride 1 mg Twice Daily Than Placebo Body System Adverse Reaction Placebo (n = 2,363) Alosetron Hydrochloride 1 mg twice daily (n = 8,328) Gastrointestinal Constipation 6% 29% Abdominal discomfort and pain 4% 7% Nausea 5% 6% Gastrointestinal discomfort and pain 3% 5% Abdominal distention 1% 2% Regurgitation and reflux 2% 2% Hemorrhoids 1% 2% Gastrointestinal: Constipation is a frequent and dose-related side effect of treatment with alosetron hydrochloride [see Warnings and Precautions (5.1) ] . In clinical studies constipation was reported in approximately 29% of patients with IBS treated with alosetron hydrochloride 1 mg twice daily (n = 9,316). This effect was statistically significant compared to placebo (p < 0.0001). Eleven percent (11%) of patients treated with alosetron hydrochloride 1 mg twice daily withdrew from the studies due to constipation. Although the number of patients with IBS treated with alosetron hydrochloride 0.5 mg twice daily is relatively small (n = 243), only 11% of those patients reported constipation and 4% withdrew from clinical studies due to constipation. Among the patients treated with alosetron hydrochloride 1 mg twice daily who reported constipation, 75% reported a single episode and most reports of constipation (70%) occurred during the first month of treatment, with the median time to first report of constipation onset of 8 days. Occurrences of constipation in clinical trials were generally mild to moderate in intensity, transient in nature and resolved either spontaneously with continued treatment or with an interruption of treatment. However, serious complications of constipation have been reported in clinical studies and in post-marketing experience [see Boxed Warning and Warnings and Precautions (5.1) ] . In Studies 1 and 2, 9% of patients treated with alosetron hydrochloride reported constipation and 4 consecutive days with no bowel movement [see Clinical Studies (14.2) ] . Following interruption of treatment, 78% of the affected patients resumed bowel movements within a 2-day period and were able to re-initiate treatment with alosetron hydrochloride. Hepatic: A similar incidence in elevation of ALT (> 2-fold) was seen in patients receiving alosetron hydrochloride or placebo (1.0% vs. 1.2%). A single case of hepatitis (elevated ALT, AST, alkaline phosphatase and bilirubin) without jaundice in a patient receiving alosetron hydrochloride was reported in a 12-week study. A causal association with alosetron hydrochloride has not been established. Long-Term Safety: Patient experience in controlled clinical trials is insufficient to estimate the incidence of ischemic colitis in patients taking alosetron hydrochloride for longer than 6 months. Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome: Table 2 summarizes the gastrointestinal adverse reactions from 1 repeat-dose study in female patients with severe diarrhea-predominant IBS who were treated for 12 weeks. The adverse reactions in Table 2 were reported in 3% or more of patients who received alosetron hydrochloride and occurred more frequently with alosetron hydrochloride than with placebo. Other events reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included upper respiratory tract infection, viral gastroenteritis, muscle spasms, headaches and fatigue. Table 2: Gastrointestinal Adverse Reactions Reported in ≥ 3% of Women with Severe Diarrhea-Predominant Irritable Bowel Syndrome and More Frequently on Alosetron Hydrochloride Than Placebo Adverse Reaction Placebo (n = 176) Alosetron Hydrochloride 0.5 mg once daily (n = 175) Alosetron Hydrochloride 1 mg once daily (n = 172) Alosetron Hydrochloride 1 mg twice daily (n = 176) Constipation 5% 9% 16% 19% Abdominal pain 3% 5% 6% 7% Diarrhea 2% 3% 2% 2% Hemorrhoidal hemorrhage 2% 3% 2% 2% Flatulence 2% 2% 1% 3% Hemorrhoids 2% 1% 1% 3% Abdominal pain upper 1% 3% 1% 1% Adverse reactions reported in another study of 701 women with severe diarrhea-predominant IBS were similar to those shown in Table 2. Gastrointestinal adverse reactions reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included constipation (14% and 10% of patients taking alosetron hydrochloride 1 mg twice daily or 0.5 mg as needed, respectively, compared with 2% taking placebo), abdominal pain, nausea, vomiting and flatulence. Other events reported in 3% or more of patients who received alosetron hydrochloride and occurring more frequently with alosetron hydrochloride than with placebo included nasopharyngitis, sinusitis, upper respiratory tract infection, urinary tract infection, viral gastroenteritis and cough. Constipation: Constipation was the most frequent adverse reaction among women with severe diarrhea-predominant IBS represented in Table 2. There was a dose response in the groups treated with alosetron hydrochloride in the number of patients withdrawn due to constipation (2% on placebo, 5% on 0.5 mg once daily, 8% on 1 mg once daily and 11% on 1 mg twice daily). Among these patients with severe diarrhea-predominant IBS treated with alosetron hydrochloride who reported constipation most (75%) reported one episode which occurred within the first 15 days of treatment and persisted for 4 to 5 days. Other Events Observed During Clinical Evaluation of Alosetron Hydrochloride: During its assessment in clinical trials, multiple and single doses of alosetron hydrochloride were administered, resulting in 11,874 subject exposures in 86 completed clinical studies. The conditions, dosages and duration of exposure to alosetron hydrochloride varied between trials and the studies included healthy male and female volunteers as well as male and female patients with IBS and other indications. In the listing that follows, reported adverse reactions were classified using a standardized coding dictionary. Only those events that an investigator believed were possibly related to alosetron hydrochloride, occurred in at least 2 patients and occurred at a greater frequency during treatment with alosetron hydrochloride than during placebo administration are presented. Serious adverse reactions occurring in at least 1 patient for whom an investigator believed there was reasonable possibility that the event was related to treatment with alosetron hydrochloride and occurring at a greater frequency in patients treated with alosetron hydrochloride than placebo-treated patients are also presented. In the following listing, events are categorized by body system. Within each body system, events are presented in descending order of frequency. The following definitions are used: infrequent adverse reactions are those occurring on one or more occasion in 1/100 to 1/1,000 patients; rare adverse reactions are those occurring on one or more occasion in fewer than 1/1,000 patients. Although the events reported occurred during treatment with alosetron hydrochloride, they were not necessarily caused by it. Blood and Lymphatic: Rare: Quantitative red cell or hemoglobin defects and hemorrhage. Cardiovascular: Infrequent: Tachyarrhythmias. Rare: Arrhythmias, increased blood pressure and extrasystoles. Drug Interaction, Overdose and Trauma: Rare: Contusions and hematomas. Ear, Nose and Throat: Rare: Ear, nose and throat infections; viral ear, nose and throat infections; and laryngitis. Endocrine and Metabolic: Rare: Disorders of calcium and phosphate metabolism, hyperglycemia, hypothalamus/pituitary hypofunction, hypoglycemia and fluid disturbances. Eye: Rare: Light sensitivity of eyes. Gastrointestinal: Infrequent: Hyposalivation, dyspeptic symptoms, gastrointestinal spasms, ischemic colitis [see Warnings and Precautions (5.2) ] and gastrointestinal lesions. Rare: Abnormal tenderness, colitis, gastrointestinal signs and symptoms, proctitis, diverticulitis, positive fecal occult blood, hyperacidity, decreased gastrointestinal motility and ileus, gastrointestinal obstructions, oral symptoms, gastrointestinal intussusception, gastritis, gastroduodenitis, gastroenteritis and ulcerative colitis. Hepatobiliary Tract and Pancreas: Rare: Abnormal bilirubin levels and cholecystitis. Lower Respiratory: Infrequent: Breathing disorders. Musculoskeletal: Rare: Muscle pain; muscle stiffness, tightness and rigidity; and bone and skeletal pain. Neurological: Infrequent: Hypnagogic effects. Rare: Memory effects, tremors, dreams, cognitive function disorders, disturbances of sense of taste, disorders of equilibrium, confusion, sedation and hypoesthesia. Non-Site Specific: Infrequent: Malaise and fatigue, cramps, pain, temperature regulation disturbances. Rare: Burning sensations, hot and cold sensations, cold sensations and fungal infections. Psychiatry: Infrequent: Anxiety. Rare: Depressive moods. Reproduction: Rare: Sexual function disorders, female reproductive tract bleeding and hemorrhage, reproductive infections and fungal reproductive infections. Skin: Infrequent: Sweating and urticaria. Rare: Hair loss and alopecia; acne and folliculitis; disorders of sweat and sebum; allergic skin reaction; eczema; skin infections; dermatitis and dermatosis; and nail disorders. Urology: Infrequent: Urinary frequency. Rare: Bladder inflammation; polyuria and diuresis; and urinary tract hemorrhage. 6.2 Post-marketing Experience In addition to events reported in clinical trials, the following events have been identified during use of alosetron hydrochloride in clinical practice. Because they were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to alosetron hydrochloride. Gastrointestinal : Impaction, perforation, ulceration, small bowel mesenteric ischemia. Neurological : Headache. Skin : Rash.

12.3 Pharmacokinetics The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 mg to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily. Absorption: Alosetron was rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range, 30% to > 90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1 mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurred at 1 hour. In young women, the mean peak plasma concentration was approximately 9 ng/mL, with a similar time to peak. Plasma concentrations were 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men). Food Effects: Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes [see Dosage and Administration (2.1) ] . Distribution: Alosetron demonstrates a volume of distribution of approximately 65 L to 95 L. Plasma protein binding is 82% over a concentration range of 20 ng/mL to 4,000 ng/mL. Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in patients with IBS confirmed that alosetron clearance is minimally influenced by doses up to 8 mg. Renal elimination of unchanged alosetron accounts for only 13% of the dose. Renal clearance is approximately 112 mL/min. A study with 14 C-labeled alosetron in Caucasian males (n = 3) and females (n = 3) and an Asian male (n = 1) showed similar serum metabolite profiles. Unchanged alosetron was the major component in serum, with other metabolites being present at low concentrations, none amounting to more than 15% of the unmetabolized alosetron concentration. The circulating metabolites were identified as 6-hydroxy glucuronide, 6-hydroxy sulphate, 7-hydroxy sulphate, hydroxymethyl imidazole and mono- and bis-oxygenated imidazole derivatives of alosetron. The metabolites are unlikely to contribute to the biological activity of alosetron. Of the circulating Phase I metabolites, only the hydroxymethyl imidazole has weak pharmacological activity, around 10-fold less potent than alosetron. Total recovery of radioactivity in the excreta was 85% ± 6%. The majority of the radiolabeled dose is excreted in the urine (74% ± 5%). The major urinary metabolites were the 6-hydroxy glucuronide and the mono- and bis-oxygenated imidazole derivatives of alosetron. 11% ± 4% of the radiolabeled dose was excreted in the feces with less than 1% of the dose being excreted as the unchanged alosetron. Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%) and 1A2 (10%). Non–CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism (62% to 97% of alosetron clearance) based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking and inhibition of clearance by fluvoxamine [see Contraindications (4) , Drug Interactions (7) ] .